INTESTINAL ABSORPTION AND PRESYSTEMIC DISPOSITION OF SILDENAFIL CITRATE IN THE RABBIT: EVIDENCE FOR SITEDEPENDENT ABSORPTIVE CLEARANCE

Abstract

Sildenafil citrate is the first oral treatment of erectile dysfunction. Its oral bioavailability is about 40%. This research characterized the intestinal transport parameters of sildenafil citrate in rabbit using in situ intestinal perfusion technique. This was studied in four different anatomical sites, namely duodenum, jejunoileum, ascending-colon, and rectum. The results revealed the highest absorptive clearance in the jejunoileum. The values of permeability area product normalized to segment length (ml/min cm) were 0.0101, 0.0063, 0.0059 and 0.0023 and those of percentage absorbed were 67.95, 32.27, 23 and 5.03 in jejunoileum, duodenum, ascending colon, and rectum respectively. The values of the length (cm) required for complete absorption were 87.58, 137.23, 153.27, and 384.09 for each segment in the same order. The absorptive clearance did not correlate with the net water flux in the four anatomical regions studied, indicating mainly passive diffusion mechanism through transcellular pathway. The plasma sildenafil concentrations achieved during intestinal perfusion experiments and sildenafil total body clearance in rabbit were used to calculate the fraction of sildenafil that reached the systemic circulation relative to the amount disappeared from the intestinal segment. Only 34% of sildenafil disappeared from the intestinal segment appeared in the systemic circulation indicating that the presystemic elimination of slidenafil is 66%. These results confirm that the incomplete bioavailability of sildenafil is mainly due presystemic elimination.